Glucagon lowers glycemia when β-cells are active

Area of Science:

• Endocrinology
• Metabolism
• Physiology

Background:

• Glucagon and insulin are traditionally viewed as having opposing effects on blood glucose.
• Recent research suggests glucagon may stimulate insulin secretion, particularly in fasting or hypoglycemic conditions.
• The role of glucagon in the postprandial (fed) state, where both hormones are secreted, remains less understood.

Purpose of the Study:

• To investigate the hypothesis that glucagon stimulates insulin secretion and reduces blood glucose in the fed state.
• To elucidate the role of glucagon in glucose regulation following mixed-nutrient meals.
• To determine if glucagon acts as an insulinotropic hormone in the postprandial period.

Main Methods:

• Administration of exogenous glucagon to fed wild-type (WT) and genetically modified mice (Gcgr:Glp1rβcell-/-).
• Administration of alanine, a glucagon secretagogue, to fasted and fed WT and Gcgr:Glp1rβcell-/- mice.
• Monitoring of blood glucose, insulin, and glucagon levels in response to interventions.

Main Results:

• Exogenous glucagon administration in fed conditions robustly stimulated insulin secretion and lowered blood glucose.
• Mice lacking both glucagon and GLP-1 receptors on beta-cells (Gcgr:Glp1rβcell-/-) did not show enhanced insulin secretion or glucose reduction with exogenous glucagon.
• Alanine administration decreased glycemia in fed WT mice, accompanied by elevated insulin and glucagon, but increased glycemia in fasted WT or fed Gcgr:Glp1rβcell-/- mice.

Conclusions:

• Glucagon functions as an insulinotropic hormone in the fed state, enhancing insulin secretion.
• Glucagon complements insulin action to maintain euglycemia (normal blood glucose levels) after meals.
• This study reframes the understanding of glucagon's role in glucose homeostasis, highlighting its cooperative function with insulin.